Search

Intrauterine growth restriction in late pregnancy can contribute to adverse long-term metabolic health in the offspring. In the present study we used an animal (sheep) model of maternal dietary manipulation in late pregnancy, combined with exposure of the offspring to a low-activity, obesogenic environment after weaning, to characterise the effects on glucose homeostasis. Dizygotic twin-pregnant sheep were either fed to 60% of requirements (nutrient restriction (R)) or fed ad libitum (~140% of requirements (A)) from 110 days gestation until term (~147 days). After weaning (~3 months of age), the offspring were kept in either a standard (in order to remain lean) or low-activity, obesogenic environment. R mothers gained less weight and produced smaller offspring. As adults, obese offspring were heavier and fatter with reduced glucose tolerance, regardless of maternal diet. Molecular markers of stress and autophagy in liver and adipose tissue were increased with obesity, with gene expression of hepatic glucose-related protein 78 (Grp78) and omental activation transcription factor 6 (Atf6), Grp78 and ER stress degradation enhancer molecule 1 (Edem1) only being increased in R offspring. In conclusion, the adverse effect of juvenile-onset obesity on insulin-responsive tissues can be amplified by previous exposure to a suboptimal nutritional environment in utero, thereby contributing to earlier onset of insulin resistance.

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity., (© 2015 Society for Endocrinology.)

Sex is a major factor determining adipose tissue distribution and the subsequent adverse effects of obesity-related disease including type 2 diabetes. The role of gender on juvenile obesity and the accompanying metabolic and inflammatory responses is not well established. Using an ovine model of juvenile onset obesity induced by reduced physical activity, we examined the effect of gender on metabolic, circulatory, and related inflammatory and energy-sensing profiles of the major adipose tissue depots. Despite a similar increase in fat mass with obesity between genders, males demonstrated a higher storage capacity of lipids within perirenal-abdominal adipocytes and exhibited raised insulin. In contrast, obese females became hypercortisolemic, a response that was positively correlated with central fat mass. Analysis of gene expression in perirenal-abdominal adipose tissue demonstrated the stimulation of inflammatory markers in males, but not females, with obesity. Obese females displayed increased expression of genes involved in the glucocorticoid axis and energy sensing in perirenal-abdominal, but not omental, adipose tissue, indicating a depot-specific mechanism that may be protective from the adverse effects of metabolic dysfunction and inflammation. In conclusion, young males are at a greater risk than females to the onset of comorbidities associated with juvenile-onset obesity. These sex-specific differences in cortisol and adipose tissue could explain the earlier onset of the metabolic-related diseases in males compared with females after obesity.

Obesity is an independent risk factor for developing chronic kidney disease. Toll-like receptor 4 (TLR4), interleukin (IL)-18, and uncoupling protein 2 (UCP2) are important components of the innate immune system mediating inflammatory renal damage. Early to midgestation maternal nutrient restriction appears to protect the kidney from the deleterious effects of early onset obesity, although the mechanisms remain unclear. We examined the combined effects of gestational maternal nutrient restriction during early fetal kidney development and early onset obesity on the renal innate immune response in offspring. Pregnant sheep were randomly assigned to a normal (control, 100%) or nutrient-restricted (NR, 50%) diet from days 30 to 80 gestation and 100% thereafter. Offspring were killed humanely at 7 days or, following rearing in an obesogenic environment, at 1 yr of age, and renal tissues were collected. IL-18 and TLR4 expression were strongly correlated irrespective of intervention. Seven-day NR offspring had significantly lower relative renal mass and IL-18 mRNA expression. At 1 yr of age, obesity resulted in increased mRNA abundance of TLR4, IL-18, and UCP2, coupled with tubular atrophy and greater immunohistological staining of glomerular IL-6 and medullary tumor necrosis factor (TNF)-alpha. NR obese offspring had a marked reduction of TLR4 abundance and renal IL-6 staining. In conclusion, maternal nutrient restriction during early fetal kidney development attenuates the effects of early onset obesity-related nephropathy, in part, through the downregulation of the innate inflammatory response. A better understanding of maternal nutrition and the in utero nutritional environment may offer therapeutic strategies aimed at reducing the burden of later kidney disease.

Background: Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese., Methods/principal Findings: Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1-65 days; LEE, n = 6) or late (65-128 days; LEL, n = 7) gestation (term approximately 147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years). Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC) (from 133 to 341 [s.e.d. 26] ng.ml(-1).120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1)) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1); LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism., Conclusions: This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young prenatally 'programmed' animals so long as weight is adequately controlled. Nutritional excess in adulthood exacerbates any programmed phenotype, indicating greater vigilance over weight control is required for those individuals exposed to nutritional thrift during gestation.

Childhood obesity has reached epidemic proportions. Obesity is an independent risk factor for the development of end-stage renal disease. Endoplasmic reticulum stress and subsequent activation of the unfolded protein response (UPR) are implicated in the development of adipose tissue dysregulation and type 2 diabetes mellitus in obesity. The present study explored the impact of adolescent-onset obesity on the UPR after obesity-related hypertension and nephropathy, using an ovine model in which obesity was induced by increased food intake and reduced activity. Obese young adults had a higher mean arterial pressure (lean, 89.6+/-1.7 mm Hg versus obese, 101+/-3.0 mm Hg; P<0.01) and greater sensitivity to low physiological doses of angiotensin II. Obesity increased the glomerular area and was associated with activation of the UPR in renal cells with a greater abundance of glucose-regulated protein 78, C/EBP homologous protein, Bax, phosphorylated c-Jun amino-terminal kinase, and activating transcription factor 6 (all P<0.05). In addition, there was a marked upregulation of proinflammatory genes, most notably those involved in macrophage signaling. Reactive oxygen species production and handling were also perturbed in obese adults. Renal endoplasmic reticulum stress was positively correlated with macrophage content (r=0.83; P<0.001), phosphorylated c-Jun amino-terminal kinase (r=0.73; P<0.01), and adiposity (r=0.71; P<0.01). In conclusion, adolescent-onset, obesity-related renal endoplasmic reticulum stress was associated with activation of the UPR, apoptosis, and inflammation, potentially increasing the associated renal damage observed in young adults. The UPR may prove to be a useful therapeutic target for the treatment and prevention of obesity-related nephropathy and associated hypertension, thereby reducing the burden of end-stage renal disease.

Maternal diet during pregnancy can program an offspring's risk of disease in later life. Obesity adversely alters renal and adipose tissue function, resulting in chronic kidney disease and insulin resistance, respectively, the latter associated with dysregulation of the unfolded protein response (UPR). In view of the current obesity epidemic, we explored the combined effects of in utero early- to midgestational nutrient restriction and postnatal obesity on the UPR in ovine juvenile offspring. Nutrient restriction was coincident with fetal kidney development but prior to exponential adipose tissue deposition. Nutrient restricted (NR) and normal diet (control) offspring were exposed to an obesogenic environment throughout adolescence, resulting in similar degrees of juvenile obesity. NR offspring showed enhanced adipose tissue dysregulation characterized by activation of the UPR, perturbed insulin signaling, and marked inflammation, as demonstrated by increased abundance of crownlike structures and proinflammatory genes. Conversely, in renal tissue NR offspring had marked attenuation of cellular stress and inflammation evident as reduced activation of the UPR, down-regulation of proinflammatory genes, and less histological damage. In conclusion, obesity-related activation of the UPR can be determined by the in utero nutritional environment, demonstrating organ-specific effects dependent on the developmental phase targeted within the fetus.

Mans ability to capture, harness and store energy most efficiently as fat in adipose tissue has been an evolutionary success story for the majority of human existence. Only over the last 30-40 years has our remarkable metabolic efficiency been revealed as our energy balance increasingly favours storage without regular periods of depletion. Historical records show us that while the composition of our diet has changed markedly over this time, our overall energy intake has significantly reduced. The inevitable conclusion therefore is that habitual physical activity and thus energy expenditure has reduced by a greater extent. Recent studies have illustrated how the finely tuned long-term control of energy intake and of energy expenditure are both developmentally plastic and susceptible to environmentally-induced change that may persist with that individual throughout their adult life, invariably rendering them more susceptible to greater adipose tissue deposition. The central role that lean body mass has upon the 'gating' of energy sensing and the importance of regular physical activity for its potential to reduce the burden of a 'thrifty phenotype' will be briefly discussed in the present review.

As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all., (Copyright (c) 2005 Wiley-Liss, Inc.)

It is apparent from epidemiological studies that the timing of maternal nutrient restriction has a major influence on outcome in terms of predisposing the resulting offspring to adult obesity. The present review will consider the extent to which maternal age, parity and nutritional restriction at defined stages of gestation can have important effects on fat deposition and endocrine sensitivity of adipose tissue in the offspring. For example, in 1-year-old sheep the offspring of juvenile mothers have substantially reduced fat deposition compared with those born to adult mothers. Offspring of primiparous adult mothers, however, show increased adiposity compared with those born to multiparous mothers. These offspring of multiparous ewes show retained abundance of the brown adipose tissue-specific uncoupling protein 1 at 1 month of age. A stimulated rate of metabolism in brown fat of these offspring may act to reduce adipose tissue deposition in later life. In terms of defined windows of development that can programme adipose tissue growth, maternal nutrient restriction targetted over the period of maximal placental growth results in increased adiposity at term in conjunction with enhanced abundance of mRNA for the insulin-like growth factor-I and -II receptors. In contrast, nutrient restriction in late gestation, coincident with the period of maximal fetal growth, has no major effect on adiposity but results in greater abundance of specific mitochondrial proteins, i.e. voltage-dependent anion channel and/or uncoupling protein 2. These adaptations may increase the predisposal of these offspring to adult obesity. Increasing maternal nutrition in late gestation, however, can result in proportionately less fetal adipose tissue deposition in conjunction with enhanced abundance of uncoupling protein 1.